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15β-substituted estrone derivatives as selective inhibitors of 17β-hydroxysteroid-dehydrogenases, method of preparation and use thereof

a technology of hydroxysteroid dehydrogenases and estrone derivatives, which is applied in the field of 15substituted estrone derivatives as selective inhibitors of 17hydroxysteroid dehydrogenases, method of preparation and use thereof, can solve the problems of recurrence, resistance, and large effort still dedicated to searching, and achieve the effect of not cytotoxi

Active Publication Date: 2020-09-01
INST OF ORGANIC CHEM & BIOCHEMISTRY OF THE ACAD OF SCI OF THE CZECH REPUBLIC +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0038]The compounds according to the present invention exhibit a unique set of properties, thanks to which they can be useful in therapy and diagnosis of estrogen-dependent diseases. They are selective inhibitors of 17βHSD, they do not have estrogenic activity and they are generally not cytotoxic. By selective inhibition of 17β-hydroxysteoid dehydrogenases (17βHSD), having a key role in the formation of biologically active estrogens and androgens, they may dramatically influence many processes in the body, in particular cell proliferation and differentiation.

Problems solved by technology

A great deal of effort is still dedicated to searching for substances that are capable of influencing the course of such illnesses.
This is due either to the absence of an appropriate therapeutic substance or to the disadvantages of existing therapeutic options used in the treatment of hormone-sensitive diseases.
These include, in particular, adverse effects, the emergence of resistance in long-term administration, and, last but not least, the frequent relapse of the disease.
Since the effect of 17βHSD5 has been demonstrated on the progression of both steroid-sensitive and non-sensitive carcinomas, selective inhibition of 17βHSD5 has long been one of the challenges for further research.
The disadvantage of long-term SERM and SEEM treatment is a frequent occurrence of serious side effects.
Although research in this area is very intense and involves countless in vitro and in vivo studies, no selective 17βHSD1 inhibitor has so far been in the clinical phase of testing as a potential therapeutic agent for the treatment of estrogen-dependent types of diseases (Poirier, D.
However, improvement in inhibitory activity against 17βHSD1 was not achieved (Ciobanu, L. C.; Poirier, D.

Method used

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  • 15β-substituted estrone derivatives as selective inhibitors of 17β-hydroxysteroid-dehydrogenases, method of preparation and use thereof
  • 15β-substituted estrone derivatives as selective inhibitors of 17β-hydroxysteroid-dehydrogenases, method of preparation and use thereof
  • 15β-substituted estrone derivatives as selective inhibitors of 17β-hydroxysteroid-dehydrogenases, method of preparation and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

ldimethylsilyloxy)-estra-1,3,5(10),15-tetraen-17-one (1)

[0147]

[0148]Enone 1 was prepared according to a published method (Sakakibara, M.; Uchida, A. O. Biosci. Biotech. Biochchem 1996, 60, 3, 405) by Saegusa oxidation in 75% yield: mp 148° C.; [α]D −37.4 (c 0.203; CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.19 (s, 6H, Si—(CH3)2), 0.98 (s, 9H, (CH3)3—C), 1.11 (s, 3H, H-18), 1.55 (m, 1H, H-7a), 1.66-1.85 (m, 3H, H-8, 11a, 12a), 2.01 (m, 1H, H-12b), 2.18 (dm, 1H, J=12.9 Hz, H-7b), 2.33 (m, 1H, H-9), 2.43 (m, 1H, H-11a), 2.50 (dm, 1H, J=11.6 Hz, H-14), 2.87-2.96 (m, 2H, H-6), 6.08 (dd, 1H, J=6.0; 3.2 Hz, H-16), 6.59 (bd, 1H, J=2.7 Hz, H-4), 6.64 (dd, 1H, J=8.5; 2.7 Hz, H-2), 7.12 (d, 1H, J=8.5 Hz, H-8), 7.63 (dd, 1H, J=6.0; 1.9 Hz, H-15); 13C NMR (150.9 MHz, CDCl3) δ−4.41 (Si—(CH3)2), 181.5 (C—(CH3)3), 20.97 (C-18), 25.34 (C-11), 25.67 (C—(CH3)3), 26.68 (C-7), 29.08 and 29.19 (C-6, 12), 35.48 (C-8), 45.15 (C-9), 51.46 (C-13), 56.13 (C-14), 117.33 (C-3), 120.01 (C-4), 125.82 (C-1), 131.87 (C-16)...

example 2

ldimethylsilyloxy)-15β-vinyl-estra-1,3,5(10)-trien-17-one (2)

[0149]

[0150]To our knowledge, the preparation of 15β-vinylestrone was published only in WO200834796. We altered this method so that instead of the benzyl protecting group (giving a reaction yield of 24%) a t-butyldimethylsilyl group was now used. We succeeded to significantly increase yields of vinylestrone 2, which (after crystallization from EtOAc) are reproducibly above 90%.

[0151]Mixture of 1 mol·l−1 solution of vinylmagnesium bromide in THF (13 ml, 13.08 mmol), CuI (65 mg, 0.654 mmol) and HMPA (2.8 ml, 15.7 mmol) in CH2Cl2 (50 ml) under argon atmosphere was cooled to −78° C. A solution of enone 1 (2.5 g, 6.54 mmol) and TMSCl (1.7 ml, 13.08 mmol) in CH2Cl2 (50 ml) was added dropwise to this mixture. The reaction mixture was then slowly warmed to room temperature and stirred overnight. After adding water and dropwise addition of 1 mol·l−1 HCl, the mixture was stirred for 5 minutes, then diluted with CH2Cl2 and washed wit...

example 3

thyl-3-hydroxy-estra-1,3,5(10)-trien-17-one (3)

[0155]

[0156]Compound 3 was prepared according to the above general procedure by reacting vinylestrone 2 with styrene (56 μl). Chromatography on HPLC (30 / 70 MeCN / H2O, tR=15 min) yielded 36 mg of colorless solid 3 (numbering of the C-15 side chain in all the following examples is the same as in derivative 3): mp 153° C.; [α]D+52.6 (c 0.547; CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.03 (s, 3H, H-18), 1.35-1.55 (m, 3H, H-7a, 11a, 12a), 1.62-1.76 (m, 3H, H-8, 14, 1′a), 1.86-1.97 (m, 3H, H-7a, 12b, 1′b), 2.25 (m, 1H, H-9), 2.30-2.38 (m, 2H, H-11b, 15), 2.40 (dd, 1H, J=19.3; 2.8 Hz, H-16a), 2.49 (dd, 1H, J=19.3; 8.1 Hz, H-16b), 2.54 (ddd, 1H, J=13.6; 9.2; 7.1 Hz, H-2′a), 2.75 (ddd, 1H, J=13.6; 9.8; 5.2 Hz, H-2′b), 2.80-2.93 (m, 2H, H-6), 4.82 (bs, 1H, OH), 6.59 (dm, 1H, J=2.8 Hz, H-4), 6.63 (ddm, 1H, J=8.4; 2.8 Hz, H-2), 7.13 (dd, 1H, J=8.5; 1.1 Hz, H-1), 7.18 (m, 2H, H-2″), 7.21 (m, 1H, H-4″), 7.30 (m, 2H, H-3″); 13C NMR (150.9 MHz, CDCl3) δ 17.71 ...

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Abstract

15β-substituted derivatives of estrone of general formula I wherein R1, R2, R3, R4, R5 are independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenalkyl, halogen, COOR6 wherein R6 is C1-C4 alkyl; H, OH; optionally, R3, R4 and R5 are each formed by a hydrogen atom, while R1 and R2 together form an aryl group, preferably naphthyl, in which the aromatic ring in position C-15 can be mono-, di-, tri-, tetra- and penta-substituted with substituents R1-R5. Compounds of the invention may be used for diagnosis and possibly also for the treatment of estrogen-dependent diseases.

Description

FIELD OF ART[0001]The present invention involves the preparation and utilization of novel ligands, selectively inhibiting the 17β-hydroxysteroid dehydrogenase enzymes (17βHSD). Compounds which selectively regulate 17βHSD activity may be an effective component of pharmaceutical compositions, particularly compositions useful for the diagnosis and treatment of estrogen-dependent types of diseases. The present invention further relates to their method of preparation and to the use thereof.BACKGROUND ART[0002]HSD enzymes belong to the group of NADP(H) / NAD(H) dependent oxidoreductases that regulate in the body the conversion of ketosteroids to hydroxysteroids and vice versa in a process called steroidogenesis. 17βHSD allow this oxidation-reduction process at the C-17 position of the steroid skeleton. Reduction of the C-17-oxo group of steroids turns a biologically not very active estrone (E1) into a highly potent 17β-estradiol (E2) as well as 4-androsten-3,17-dione into testosterone (T) a...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/566C07J1/00
CPCC07J1/0059A61P15/00A61P15/08A61P15/18A61P17/10A61P17/14A61P35/00A61P5/24A61P5/30A61P5/32
Inventor KOTORA, MARTINPRCHALOVA, EVAADAMSKI, JERZYMOELLER, GABRIELESTEPANEK, ONDREJBARTUNEK, PETRSEDLAK, DAVIDHAJDUCH, MARIANDZUBAK, PETR
Owner INST OF ORGANIC CHEM & BIOCHEMISTRY OF THE ACAD OF SCI OF THE CZECH REPUBLIC